Synthetic quinolone antibacterial compounds exhibit broad antibacterial spectrum and potent antibacterial activity, and thus have been widely employed as various therapeutic drugs for bacterial infections (see Non-Patent Document 1). Particularly, compounds such as levofloxacin, ofloxacin, ciprofloxacin, moxifloxacin, and trovafloxacin have been widely employed by virtue of excellent antibacterial activity, because of their broad antibacterial spectrum and high antibacterial activity. Similarly, sitafloxacin, a compound represented by formula (I) given hereinbelow, and a compound represented by formula (II) described in the Examples hereinbelow also exhibit excellent antibacterial activity and also exhibit excellent antibacterial activity against drug-resistant bacteria, and thus are promising candidates for excellent antibacterial drugs.
Particularly, a quinolone compound (7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid) having a structure represented by formula (I) (hereinafter the compound may be abbreviated as “compound (I)”):
exhibits excellent antibacterial activity; for example, high antibacterial activity against drug-resistant Gram-positive bacteria such as methicillin-resistant staphylococci, penicillin-resistant pneumococci, and vancomycin-resistant enterococci. In addition, compound (I) has high safety, and is expected to exhibit excellent therapeutic effect (see Patent Document 1). Similar to compound (I), compound (II) is an excellent quinolone compound which exhibits excellent antibacterial activity against, for example, drug-resistant bacteria, and has high safety (see Patent Document 2).
Quinolone compounds, particularly those exhibiting excellent antibacterial activity against drug-resistant bacteria, are expected to exhibit excellent therapeutic effects on severe infections by virtue of their antibacterial properties. In many cases, a quinolone compound must be intravascularly administered in the form of solution to patients with severe infections. Therefore, such intravascular administration requires a drug solution containing a quinolone compound; i.e., requires provision of a lyophilized preparation which contains a quinolone compound (i.e., a drug substance) and a pH-adjusting agent as a sole additive, and which is reconstituted upon use.
One known method for preparing a lyophilized preparation includes an annealing step. In the annealing step, the temperature of a frozen product of aqueous raw material solution obtained through a cooling step (i.e., an initial step) is temporarily elevated, and then the solution is maintained for a predetermined period of time. As has been known, a lyophilized preparation which contains an excipient as an additive or as a sole additive and which has been prepared through a method with an annealing step may differ, in terms of reconstituting property, from a lyophilized preparation prepared through a method without annealing step. However, in the above case, the effect of the annealing step does not exhibit a consistent tendency in terms of reconstituting property and actually may be an improving effect or a deteriorating effect. Thus, the effect of the annealing step on reconstituting property of a lyophilized preparation varies depending on a substance contained in the preparation (see Non-Patent Documents 2 and 3).
Intrinsically, a bulking agent is an ingredient for improving the reconstituting property of a lyophilized preparation. The reconstituting property of a lyophilized preparation containing a bulking agent has been known to be affected by an annealing step. However, it has not yet been elucidated the effect of an annealing step on the reconstituting property of a lyophilized preparation which contains no excipient and which has been produced through a method with the annealing step.    Patent Document 1: WO 02/40478    Patent Document 2: Specification of International Application PCT/JP2006/310069    Non-Patent Document 1: Hooper D. C. and Rubinstein E. (eds) 3rd Edition Quinolone Antimicrobial Agents. 2003. ASM Press Books    Non-Patent Document 2: Journal of Pharmaceutical Sciences, Vol. 90, No. 7, pp. 872-887, 2001    Non-Patent Document 3: Journal of Pharmaceutical Sciences, Vol. 92, No. 4, pp. 715-729, 2003